This K05 competing renewal application seeks continued support for the applicant's research and junior faculty mentoring program, which investigates gene-environment interplay in alcohol use disorder onset, course and consequences, with a particular emphasis on understanding female AUD. The candidate has been continuously funded by NIAAA as R01 PI since 1988, and has over 500 publications, many highly cited. He has led many investigations on the genetic epidemiology of alcohol use disorder. His career development plan seeks to acquire knowledge to further expand the reach of his research, to take advantage of emerging opportunities in whole genome sequencing (for gene discovery using his Australian twin-family series), metagenomics (including its potential for biomarker development), spatial epidemiology (to allow merging of ecological data on neighborhood alcohol-related risk-factors with existing cohort studies), and neuroimaging (to maximize the value for the alcohol research community of his role in the Human Connectome Project): in other words, seeks to continue to improve characterization of genetic (perhaps including metagenomic) risks, characterization of environmental risks, and phenotyping, to further gene-environment interplay understanding, taking advantage of the unique institutional environment for these areas of research. He will mentor 3-5 junior faculty with research focused on varied aspects of AUD risk: e.g. (i) predictors of remission in women with severe alcoholism; (ii) childhood sexual abuse effects on alcohol use patterning; (iii) statistical modeling to detect excessive drinking effects on human brain functional connectivity; (iv) maternal alcoholism, parental separation, and early-onset drinking; (v) processes underlying alcoholism-binge eating comorbidity. His research plan focuses on two priority areas - extension of his follow-up of the MOAFTS twin cohort, to focus on predictors of remission of alcohol problems; and high-risk research using fecal sample collection from current and former excessive drinkers and BMI-matched controls, combined with bacterial 16S rRNA gene sequencing, to determine whether chronic alcohol effects on gut microbial ecology can lead to new approaches for the detection of excessive drinking.